Ascorbate status modulates reticuloendothelial iron stores and response to deferasirox iron chelation in ascorbate-deficient rats
Ascorbate status modulates reticuloendothelial iron stores and response to deferasirox iron chelation in ascorbate-deficient rats
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DOI：
10.1016/j.exphem.2012.06.005
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发表时间：
2012-10-01
影响因子：
2.6
通讯作者：
Wood, John C.
中科院分区：
文献类型：
--
作者：
Brewer, Casey;Otto-Duessel, Maya;Wood, John C.
铁螯合对慢性输血的患者至关重要，以防止铁过载引起的毒性并清除多余的铁。地拉罗司（DFX）是美国最常用的铁螯合剂;然而，一些患者对DFX治疗相对难治。我们推测，维生素C的补充将提高输血铁DFX治疗的可用性，通过促进铁的氧化还原循环，增加其可溶性亚铁的形式，并促进其从网状内皮细胞的释放。成骨营养不良大鼠（n = 54）给予右旋糖酐铁注射10周。在铁负荷（n = 18）、12周假螯合（n = 18）和12周DFX螯合（n = 18）（75 mg/kg/天）后测量心脏和肝脏铁水平。在食物中补充150 ppm、900 ppm和2250 ppm的抗坏血酸以模拟广泛的抗坏血酸状态;血浆抗坏血酸水平分别为5.4 +/-1.9、8.2 +/-1.4、23.6 +/-9.8 μ M（p < 0.0001）。最严重的抗坏血酸缺乏导致网状内皮细胞滞留，在铁负荷结束时使肝脏总铁减少29%（p < 0.05），并在12周的假螯合期间限制心脏和肝脏巨噬细胞的铁再分布。最重要的是，2250 ppm的抗坏血酸补充提高了DFX效率，使DFX比900 ppm或150 ppm的抗坏血酸补充多去除21%的肝铁（p < 0.05）。我们得出结论，维生素C状态调节铁从网状内皮系统的释放，并与DFX螯合效率呈正相关。我们的研究结果表明，抗坏血酸状态应探讨患者对DFX反应不满意。(C)2012 ISEH -血液学和干细胞学会。爱思唯尔公司出版
Iron chelation is essential to patients on chronic blood transfusions to prevent toxicity from iron overload and remove excess iron. Deferasirox (DFX) is the most commonly used iron chelator in the United States; however, some patients are relatively refractory to DFX therapy. We postulated that vitamin C supplementation would improve the availability of transfusional iron to DFX treatment by promoting iron's redox cycling, increasing its soluble ferrous form and promoting its release from reticuloendothelial cells. Osteogenic dystrophy rats (n = 54) were given iron dextran injections for 10 weeks. Cardiac and liver iron levels were measured after iron loading (n = 18), 12 weeks of sham chelation (n = 18), and 12 weeks of DFX chelation (n = 18) at 75 mg/kg/day. Ascorbate supplementation of 150 ppm, 900 ppm, and 2250 ppm was used in the chow to mimic a broad range of ascorbate status; plasma ascorbate levels were 5.4 +/- 1.9, 8.2 +/- 1.4, 23.6 +/- 9.8 mu M, respectively (p < 0.0001). The most severe ascorbate deficiency produced reticuloenthelial retention, lowering total hepatic iron by 29% at the end of iron loading (p < 0.05) and limiting iron redistribution from cardiac and hepatic macrophages during 12 weeks of sham chelation. Most importantly, ascorbate supplementation at 2250 ppm improved DFX efficiency, allowing DFX to remove 21% more hepatic iron than ascorbate supplementation with 900 ppm or 150 ppm (p < 0.05). We conclude that vitamin C status modulates the release of iron from the reticuloendothelial system and correlates positively with DFX chelation efficiency. Our findings suggest that ascorbate status should be probed in patients with unsatisfactory response to DFX. (C) 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.